The present invention relates to a process for preparing isoxazolin-3-ylacylbenzenes, to novel intermediates and to novel processes for preparing these intermediates.
Isoxazolin-3-ylacylbenzenes are useful compounds which can be employed in the area of crop protection. 2-Alkyl-3-(4,5-dihydroisoxazol-3-yl)acylbenzenes are described, for example, in WO 98/31681, as herbicidally active compounds.
It is an object of the present invention to provide an alternative process for the preparation of 3-heterocyclyl-substituted benzoyl derivatives described in WO 98/31681. The process described in WO 98/31681 for preparing the 2-alkyl-3-(4,5-dihydroisoxazol-3-yl)acylbenzenes and their precursor (2-alkyl-3-(4,5-dihydroisoxazol-3-yl)bromobenzene derivatives) is not well suited for the preparation of these compounds on a large industrial scale, since the synthesis extends over several steps and the yield of the respective end product is relatively low, based on the starting materials employed in the first step of the synthesis.
We have found that this object is achieved by reducing the number of process steps required for preparing the 3-heterocyclyl-substituted benzoyl derivatives, compared with the process described in WO 98/31681, when the synthesis occurs via selected intermediate compounds. Moreover, the process according to the invention has the advantage that the overall yield of end products of the formula I and also for the intermediates, based on the starting materials employed, is higher than the yield in the processes described in WO 98/31681. In addition, the respective intermediates in the individual process steps can be obtained in good yield. Moreover, some of the individual process steps are advantageous for the industrial preparation of the intermediate compounds since they allow a cost-effective and economical preparation of these compounds. It is furthermore advantageous that the starting materials used are basic chemicals which are easy to prepare and which can be obtained from a number of independent suppliers of basic chemicals, even in relatively large amounts. Altogether, the process according to the invention provides a cost-effective, economical and safe industrial-scale process for preparing herbicidally active compounds of the formula I.
The present invention provides a process for preparing the compounds of the formula I 
where:
R1 is hydrogen, C1-C6-alkyl,
R2 is hydrogen, C1-C6-alkyl,
R3, R4, R5 are each hydrogen, C1-C6-alkyl or R4 and R5 together form a bond,
R6 is a heterocyclic ring,
n is 0, 1 or 2;
which comprises preparing an intermediate of the formula VI, 
in which R1, R3-R5 are each as defined above.
In subsequent reaction steps, compounds of the formula VI are converted into the corresponding 3-bromo-substituted compounds (bromobenzene derivatives), and the amino group at the phenyl ring is converted into an S(O)nR2 group, preferably sulfonyl group, giving rise to compounds of the formula X: 
The compounds of the formula X (3-(4,5-dihydroisoxazol-3-yl)bromobenzenes) are useful intermediates for preparing active compounds of the formula I. In particular, the process according to the invention gives the compounds I in the last reaction step in good yield. The compounds I are suitable, for example, for use as crop protection agents, in particular as herbicides, as described in WO 96/26206 and WO 97/35850.
The present invention particularly preferably provides a process for preparing the compounds of the formula I where R2=C1-C6-alkyl, which comprises preparing an intermediate of the formula VI.
The present invention likewise particularly preferably provides a process for preparing compounds of the formula I where R2=hydrogen, comprising the preparation of an intermediate of the formula VI.
Likewise according to the invention, it is possible to prepare compounds of the formula I or the intermediates required for this, in particular compounds of the formula VI or X, in an advantageous manner by combining one or more of the following process steps a)-g), where, with respect to the compounds of the formula I, one process step of the group of process steps a)-f) has to be involved:
a) reaction of a nitro-o-methylphenyl compound of the formula II 
xe2x80x83in which the radical R1 is as defined above, with an organic nitrite Rxe2x80x94ONO under action of a base to give the oxime of the formula III 
xe2x80x83in which the radical R1 is as defined above;
b) cyclization of the oxime of the formula III using an alkene of the formula IV 
xe2x80x83in which R3 to R5 are each as defined in claim 1, in the presence of a base to give the isoxazole of the formula V 
xe2x80x83in which R1, R3 to R5 are each as defined in claim 1;
c) reduction of the nitro group in the presence of a catalyst to give the aniline of the formula VI 
xe2x80x83in which R1, R3 to R5 are each as defined in claim 1;
d) reaction of the aniline of the formula VI with a dialkyl disulfide of the formula VII
R2xe2x80x94Sxe2x80x94Sxe2x80x94R2xe2x80x83xe2x80x83VII
xe2x80x83in the presence of an organic nitrite Rxe2x80x94ONO and, if appropriate, a catalyst to give the thioether of the formula VIII 
xe2x80x83in which R1 to R5 are each as defined in claim 1;
e) bromination of the thioether of the formula VIII with a brominating agent to give the bromothioether of the formula IX 
xe2x80x83in which R1 to R5 are each as defined in claim 1;
f) oxidation of the bromothioether of the formula IX with an oxidizing agent to give the isoxazole of the formula X 
xe2x80x83where n is the number 1 or 2,
g) if appropriate, reaction of the isoxazoline of the formula X with a compound of the formula R6xe2x80x94OH (XI) in the presence of carbon monoxide, a catalyst and a base to give the compounds of the formula I.
The process according to the invention for preparing compounds X comprises essentially one or more of the process steps a)-f) or, in the case of the compounds I, one or more of the process steps a)-g), where a process step from the group of process steps a)-f) has to be involved. Preference is given to reaction sequences which comprise either one of process steps a) or d) or else both steps a) and d).
In all cases, C1-C6-alkyl and C1-C4-alkyl are straight-chain or branched alkyl groups having 1-6 and 1-4 carbon atoms, respectively, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl. This applies analogously to the C1-C6-alkoxy group.
R1, R2 are preferably alkyl groups, in particular methyl, ethyl, isopropyl, n-propyl or n-butyl groups.
R3, R4 and R5 are preferably hydrogen. R4 and R5 together may also represent a bond, resulting in the corresponding isoxazole derivatives. In this case, R3 is preferably hydrogen.
In the definition of R6, xe2x80x9cheterocyclic ringxe2x80x9d is a saturated, unsaturated or partially unsaturated heterocycle having 1, 2 or 3 oxygen, sulfur or nitrogen atoms. Preference is given to heterocycles having two nitrogen atoms. In particular, R6 is a pyrazole radical as described in more detail in WO 98/31681. It is preferably a pyrazole attached in the 4-position which may be unsubstituted or substituted by further radicals which are chemically inert under the chosen reaction conditions. Such suitable pyrazole substituents are, for example, the following groups: hydroxyl, oxo, sulfonyloxy, C1-C6-alkyl or C1-C6-alkoxy, in particular in the 1-position C1-C4-alkyl. R6 is particularly preferably the group 1-alkyl-5-hydroxypyrazol-4-yl, in particular 1-methyl-5-hydroxypyrazol-4-yl; 1-ethyl-5-hydroxypyrazol-4-yl.
The process according to the invention is particularly suitable for preparing the following compounds of the formula I:
1-methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-methylsulfonylbenzoyl)-5-hydroxypyrazole,
1-ethyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-methylsulfonylbenzoyl)-5-hydroxypyrazole,
1-methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-ethyl-4-methylsulfonylbenzoyl)-5-hydroxypyrazole,
1-methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-propyl-4-methylsulfonylbenzoyl)-5-hydroxypyrazole,
1-methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-butyl-4-methylsulfonylbenzoyl)-5-hydroxypyrazole.
Preferred intermediates of the formula VI are the following compounds:
2-(4,5-dihydroisoxazol-3-yl)aniline,
2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline,
2-(4,5-dihydroisoxazol-3-yl)-3-ethylaniline,
2-(Isoxazol-3-yl)aniline,
2-(isoxazol-3-yl)-3-methylaniline,
2-(isoxazol-3-yl)-3-ethylaniline.
The process according to the invention is particularly suitable for preparing the following intermediates of the formula X:
3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole,
3-(3-chloro-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole,
3-(3-bromo-6-methylsulfonylphenyl)-4,5-dihydroisoxazole,
3-(3-bromo-2-ethyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole,
3-(3-bromo-2-isopropyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole,
3-(3-bromo-2-methyl-6-ethylsulfonylphenyl)-4,5-dihydroisoxazole,
3-(3-bromo-2-methyl-6-propylsulfonylphenyl)-4,5-dihydroisoxazole,
3-(3-bromo-2-methyl-6-butylsulfonylphenyl)-4,5-dihydroisoxazole,
3-(3-bromo-2-methyl-6-pentylsulfonylphenyl)-4,5-dihydroisoxazole,
3-(3-bromo-2-methyl-6-hexylsulfonylphenyl)-4,5-dihydroisoxazole.
A possible reaction sequence up to the preparation of the compounds X is summarized in the synoptical diagram below: 
Hereinbelow, the individual reaction steps are briefly illustrated in more detail.
1. Step a) 
The reaction is carried out, for example, under the following conditions: the solvents used are bipolar aprotic solvents, for example N,N-dialkylformamide, N,N-dialkylacetamide, N-methylpyrrolidone (NMP), preferably: dimethylformamide (DMF) or NMP. The temperature is from xe2x88x9260xc2x0 C. to room temperature; preferably from xe2x88x9250 to xe2x88x9220xc2x0 C.; especially preferably from xe2x88x9235 to xe2x88x9225xc2x0 C. To achieve a sufficient low melting point of the solvent system, it is also possible to use mixtures of solvents, such as, for example, with THF. The organic nitrites Rxe2x80x94ONO used are alkyl nitrites (R=alkyl), preferably n-butyl nitrite or (iso)amyl nitrite. Suitable bases are: Moalkyl, MOH, RMgX (M=alkali metal); preferably potassium methoxide (KOMe), sodium methoxide (NaOMe) or potassium tert-butoxide (KOtbutoxide). When using sodium bases, 1-10 mol % of amyl alcohol may be added, if appropriate. The stoichiometric ratios are, for example, as follows: 1-4 equivalents of base, 1-2 equivalents of Rxe2x80x94ONO; preferably 1.5-2.5 equivalents of base and 1-1.3 equivalents of Rxe2x80x94ONO; equally preferably: 1-2 equivalents of base and 1-1.3 equivalents of Rxe2x80x94ONO.
The addition is carried out, for example, according to the following metering sequence: a) nitro-o-xylene and nitrite are initially charged and the base is metered in. b) To avoid having to meter in the solid base, the base can initially be charged in DMF, and nitro-o-xylene/butyl nitrite can be added simultaneously. The metering rate for adding the base is relatively slow, so that the cooling required is reduced to a minimum. Work-up is carried out by one of the following methods: a) precipitation of the product by stirring the mixture into water or into a mineral acid/water mixture such as, for example, hydrochloric acid/water. b) Precipitation of the product by addition of a sufficient amount of water to the reaction mixture. The product is purified by extraction with toluene at from 0 to 110xc2x0 C., preferably at room temperature.
2. Step b) 
The reaction is carried out, for example, via the following mechanistic intermediates: conversion of the oxime III into an activated hydroxamic acid derivative, such as, for example, hydroxamic acid chloride, by chlorination with a chlorinating agent, conversion of the activated hydroxamic acid derivative into the nitrile oxide, such as, for example, conversion of the hydroxamic acid chloride in the presence of a base into the nitrile oxide, and subsequent cycloaddition of the alkene IV to the nitrile oxide.
This reaction is a novel process for preparing isoxazole derivatives of the formula V. Surprisingly, this process affords the isoxazalines is very good yields. Furthermore, only a few by-products are formed which, moreover, can also be removed relatively easily. Owing to this, it is possible to isolate and purify the end products in a simple manner on a large industrial scale, so that the isoxazolines can be prepared in high purity and at low cost. Hitherto, the use of known processes for preparing isoxazolines has been disadvantageous, since the isoxazalines could be obtained from the reaction of the benzaldoximes only in unsatisfactory yields. Furthermore, the processes known from the prior art frequently make use of alkali metal hypohalide-containing solutions which lead to the formation of poorly soluble and environmentally unfriendly by-products. The process according to the invention is characterized in that the use of alkali metal hypohalite-containing solutions can be dispensed with, the process thus being essentially free of alkali metal hypohalites.
The isoxazolines are prepared, for example, by the following method: initially, hydroxamic acid chloride is formed which is cyclized in a second step with an alkene, if appropriate at superatmospheric pressure, and with metered addition of base. These individual steps can also be combined in an advantageous manner in a xe2x80x9cone-pot reactionxe2x80x9d. To this end, a solvent is employed in which both partial steps proceed, for example carboxylic esters, such as ethyl acetate, chlorobenzene or acetonitrile.
The preparation of hydroxamic acid chlorides using N-chlorosuccinimide in DMF is known from the literature (Liu et al., J.Org. Chem. 1980, 45: 3916-3918). However, it is also mentioned that the conversion of o-nitrobenzaldoximes into the hydroxamic acid chlorides by chlorination gives only poor yields (Chiang, J. Org. Chem. 1971, 36: 2146-2155). The formation of benzal chloride is to be expected as a side reaction. Surprisingly, in accordance with the process described above, we have found conditions which permit preparation of the desired hydroxamic acid chlorides in excellent yields. Particularly advantageous is the use of the inexpensive chlorine.
The reaction is carried out, for example, under the following conditions: solvents: haloalkanes, such as 1,2-dichloroethane or methylene chloride; aromatics, such as benzene, toluene, chlorobenzene, nitrobenzene or xylene; polar aprotic solvents, for example N,N-dialkylformamides, -acetamides, N-methylpyrrolidone, dimethylpropylene urea; tetramethyl urea, acetonitrile, propionitrile; alcohols, such as methanol, ethanol, n-propanol or isopropanol; carboxylic acids, such as acetic acid or propionic acid; carboxylic esters, such as ethyl acetate. Preference is given to using the following solvents: acetic acid, methanol, ethanol, 1,2-dichloroethane, methylene chloride or chlorobenzene or ethyl acetate. The reaction is carried out at from xe2x88x9240xc2x0 C. to 100xc2x0 C.; preferably from xe2x88x9210 to 40xc2x0 C. or from 0 to 30xc2x0 C.; the reaction is equally preferably carried out in a temperature range of 30-60xc2x0 C., in particular 30-50xc2x0 C. Suitable halogenating agents are: N-chlorosuccinimide, elemental chlorine, preferably chlorine. The stoichiometric ratios are, for example, 1-3 equivalents of halogenating agent, preferably 1-1.5 equivalents. The metered addition is carried out, in the case of chlorine, by passing the gas through the solution, in the case of N-chlorosuccinimide (NCS) by addition as a solid or, if appropriate, in a suitable solvent.
Work-up is carried out, for example, according to the following scheme: a) without purification. The solution is employed for the next step; b) solvent exchange by distillative removal of the solvent; c) addition of water and extraction of the hydroxamic acid chloride using a suitable solvent.
By addition of bases, the hydroxamic acid chlorides are converted into the nitrile oxides. Since these compounds are unstable, the object which had to be achieved was finding conditions which permit stabilization of the nitrile oxides, and their conversion into the desired products. Surprisingly, this object can be achieved by choosing the reaction conditions below: the solvents used are: haloalkanes, such as 1,2-dichloroethane or methylene chloride; aromatics, such as benzene, toluene, chlorobenzene, nitrobenzene or xylene; polar aprotic solvents, for example, N,N-dialkylformamides, -acetamides, N-methylpyrrolidone, dimethylpropylene urea; tetramethyl urea, acetonitrile, propionitrile, carboxylic esters, such as ethyl acetate. Preference is given to using: 1,2-dichloroethane, methylene chloride, toluene, xylene, ethyl acetate or chlorobenzene.
The temperatures for the reaction are from 0xc2x0 C. to 100xc2x0 C., preferably from 0 to 50xc2x0 C. or from 0 to 30xc2x0 C.
The bases employed are: tertiary amines, for example triethylamine, cyclic amines, such as N-methylpiperidine or N,Nxe2x80x2-dimethylpiperazine, pyridine, ammonia, alkali metal carbonates, for example sodium carbonate or potassium carbonate, alkali metal bicarbonates, for example sodium bicarbonate or potassium bicarbonate, alkaline earth metal carbonates, for example calcium carbonate, alkali metal hydroxides, for example sodium hydroxide or potassium hydroxide. Preference is given to using: triethylamine, sodium carbonate, sodium bicarbonate or sodium hydroxide.
The stoichiometric ratios are, for example, 1-3 equivalents of base, preferably 1-1.5 equivalents, equally preferably 2 to 3 equivalents; 1-5 equivalents of alkene, preferably 1-2 equivalents. The metered addition is preferably carried out under a superatmospheric alkene pressure, by slowly adding the base. The reaction is carried out at from atmospheric pressure to 10 atm, preferably 0-6 atm atmospheric pressure.
3. Step c) 
This reaction is a novel chemoselective hydrogenation of a nitro group in the presence of an isoxazoline, said reaction having hitherto been unknown. Surprisingly, it has been found that the Nxe2x80x94O bond of the isoxazoline is not cleaved under the chosen reaction conditions. The catalytic hydrogenation of aromatic nitro compounds to anilines has been known for a long time (see Houben Weyl, Vol. IV/1c, p. 506 ff). On the other hand, it has also been known that the Nxe2x80x94O bond of isoxazolines can be cleaved by catalytic hydrogenation, for example using Raney-Nickel (Curran et al., Synthesis 1986, 312-315) or palladium (Auricchio et al., Tetrahedron, 43 (1987), 3983-3986) as catalyst.
The reaction is carried out, for example, under the following conditions: suitable solvents are aromatics, such as benzene, toluene, xylene; polar aprotic solvents, for example N,N-dialkylformamides, -acetamides, N-methylpyrrolidone, dimethylpropylene urea; tetramethyl urea, carboxylic esters, such as ethyl acetate, ethers, such as diethyl ether or methyl tert-butyl ether, cyclic ethers, such as tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol, n-propanol, isopropanol or n-butanol, carboxylic acids, such as acetic acid or propionic acid. Preference is given to using the following solvents: ethyl acetate, toluene, xylene, methanol, ethanol or dimethylformamide; in particular methanol or dimethylformamide. The reaction is carried out at from xe2x88x9220xc2x0 C. to 100xc2x0 C.; preferably from 0 to 50xc2x0 C., particularly preferably from 0 to 30xc2x0 C. The reaction is equally preferably carried out in a temperature range of 30-40xc2x0 C. The catalyst used is a platinum or palladium catalyst supported on activated carbon, having a content of from 0.1 to 15% by weight, based on the support of an activated carbon. If a palladium catalyst is employed, this catalyst can be doped with sulfur or selenium to achieve better selectivity. Preference is given to using platinum/activated carbon or palladium/activated carbon having a content of Pt or Pd of from 0.5 to 10% by weight.
The stoichiometric ratios for the reaction are, for example, as follows: from 0.001 to 1% by weight of platinum or palladium, based on the nitro compound; preferably from 0.01 to 1% by weight of platinum, equally preferably 0.01 to 1% by weight of palladium. The metered addition of hydrogen is carried out continuously or batchwise, preferably batchwise at from atmospheric pressure to 50 atm, preferably at atmospheric pressure to 20 atm, particularly preferably atmospheric pressure to 10 atm.
Work-up of the reaction mixture is carried out by removing the catalyst by filtration. If appropriate, the catalyst can be recycled. The solvent is distilled off. For the subsequent reaction in the next process step, the product can be used directly without further purification. If required, it is also possible to purify the product further. The product is purified, for example, according to the following scheme: if required, the aniline can be purified by taking up the residue in dilute mineral acid, for example aqueous hydrochloric acid or dilute sulfuric acid, extraction with a suitable organic extractant, for example haloalkanes, such as 1,2-dichloroethane or methylene chloride, aromatics, such as benzene, toluene, chlorobenzene or xylene, ethers, such as diethyl ether or methyl tert-butyl ether, carboxylic esters, such as ethyl acetate, and be liberated again using a base.
4. Step d) 
The reaction is carried out for compounds of the formula VIII where R2=C1-C6-alkyl under the following conditions: suitable solvents are, for example: haloalkanes, such as 1,2-dichloroethane or methylene chloride, aromatics, such as benzene, toluene, chlorobenzene, nitrobenzene, or an excess of the dialkyl disulfide as solvent. Preference is given to using an excess of the dialkyl disulfide as solvent. The temperature for the reaction is from 40xc2x0 C. to 150xc2x0 C.; preferably from 50 to 100xc2x0 C., particularly preferably from 60 to 90xc2x0 C. The reaction is carried out equally well in a temperature range of 45-75xc2x0 C., in particular in a range of 55-65xc2x0 C. The reagents used are organic nitrites (Rxe2x80x94ONO), such as, for example, alkyl nitrites, preferably n-butyl nitrite, (iso)amyl nitrite or tert-butyl nitrite. Here, R can be any organic radical which is chemically inert and has no effect on the actual reaction. R is, for example, a C1-C6-alkyl or C2-C6-alkenyl group.
The stoichiometric ratios in the reaction of the compounds are, for example, as follows: 1-3 equivalents of alkyl nitrite, preferably 1-1.5 equ. of alkyl nitrite, especially preferably 1-1.3 equ. of alkyl nitrite. Suitable catalysts are: copper powder, elemental copper in a different form, such as, for example, turnings, wire, granules, shot, rods; copper(I) salts, for example copper(I) chloride, copper(I) bromide or copper(I) iodide, copper(II) salts, or elemental iodine, particularly preferably copper powder, likewise particularly preferably copper salts. When carrying out the reaction in a solvent, 1-3 equivalents of dialkyl disulfide, preferably 1-2 equivalents, are employed. In a preferred embodiment, an excess of dialkyl disulfide is employed as solvent, which is subsequently recovered by distillation. For further conversion, the product can be used without further purification. If required, it is also possible to purify the product beforehand, by distillation or crystallization with the aid of suitable solvents, such as, for example, from diisopropyl ether.
Usually, the dialkyl disulfide, the organic nitrite and the catalyst are initially charged and the compound of the formula VI and further dialkyl disulfide are metered in. However, it is also possible to initially charge the compound of the formula VI, the dialkyl disulfide and the catalyst and to meter in the organic nitrite.
Compounds of the formula VIII where R2=hydrogen are obtained similarly to processes known from the literature, for example by diazotizing the compound of the formula VI in aqueous medium with a nitrite or in organic or aqueous/organic medium with an organic nitrite (Rxe2x80x94ONO) and reacting the diazonium salt with a metal sulfide, in particular an alkali metal sulfide, such as sodium sulfide. It is also possible to react the diazonium salt with a xanthogenate, such as, for example, potassium ethylxanthogenate, and then to hydrolyze the aryl xanthogenate formed to give the compound VIII where R2=hydrogen. Suitable for this purpose are, inter alia, ammonia, sodium hydroxide or potassium hydroxide, in particular ethanolic potassium hydroxide solution (Houben-Weyl, Vol. 9, p. 12, 4th edition).
5. Step e) 
The bromination is carried out similarly to the method described in WO 98/31676. Advantageously, the solvent used is acetic acid.
6. Step f) 
The oxidation is carried out similarly to the method described in WO 98/31676 (cf. p. 8 line 32 to p. 11, line 25).
7. Step g)
The conversion of the compound of the formula X into compounds of the formula I, which is carried out subsequently, if appropriate, is carried out by addition of R6xe2x80x94OH (XI) in the presence of carbon monoxide and a suitable catalyst and a base. If R6 is an unsubstituted or substituted pyrazole or pyrazoline ring, the reaction is preferably carried out using palladium-containing catalysts, such as, for example, Pd(O) catalyst or bis-triphenylphosphine-palladium(II) chloride.
The process is illustrated hereinbelow in more detail using the example where R6=pyrazole (XI.a) as heterocycle. In principle, however, it is also possible to use other heterocyclic compounds, such as defined initially.
The process is preferably carried out by reacting a hydroxypyrazole of the formula XI.a 
in which R7 is C1-C6-alkyl and M is hydrogen or an alkali metal atom, preferably sodium or potassium, with a bromobenzene of the formula X 
in which R1 to R5 are as defined above, in the presence of carbon monoxide, a palladium catalyst, if appropriate at least one molar equivalent of a potassium salt and, if appropriate, at least one molar equivalent of a tertiary amine of the formula XIII
xe2x80x83N(Ra)3xe2x80x83xe2x80x83XIII
in which one of the radicals Ra may represent phenyl or naphthyl and the other radicals Ra are C1-C6-alkyl, at temperatures of from 100 to 140xc2x0 C. and at a pressure of from 1 to 40 kg/cm2.
In a preferred embodiment of the process, the 5-hydroxypyrazole XI.a and the bromobenzene derivative X are employed in a molar ratio of from 1 to 2.
The 5-hydroxypyrazoles XI.a used are preferably compounds in which R7 is C1-C6-alkyl, in particular methyl or ethyl.
The 5-hydroxypyrazoles (or pyrazolinones) of the formula XI.a used as starting materials are known and can be prepared by processes known per se (cf. EP-A 240 001, WO 96/26206 and J. Prakt. Chem. 315 (1973), p. 382).
In general, the 5-hydroxypyrazole XI.a is employed in equimolar amounts or in excess, based on the bromobenzene derivative X. For economical reasons, it is expedient to avoid a large excess of 5-hydroxypyrazole. Under the reaction conditions according to the invention, a stoichiometric reaction gives the same yield as when an excess of 5-hydroxypyrazole is used. This was surprising, since in all of the examples for the process described in EP-A 344 775, a large excess of 5-hydroxypyrazole is used. In the process according to the invention, the molar ratio of 5-hydroxypyrazole to bromobenzene is preferably set to from 1 to 2 and particularly preferably to from 1.0 to 1.2.
Above 140xc2x0 C., decomposition occurs, below 100xc2x0 C., the reaction comes to a standstill. Thus, in general, the reaction is carried out in a temperature range of from 100 to 140xc2x0 C. and preferably from 110 to 130xc2x0 C.
The reaction is usually carried out at a pressure of at most up to 40 kg/cm2, preferably up to 20 kg/cm2 or else up to 10 kg/cm2 without this having an adverse effect on the reaction conditions, such as reaction temperature or reaction time, or resulting in a loss of yield. The reaction pressure is preferably at least 3 kg/cm2, in particular at least 5 kg/cm2. Exemplary pressure ranges are: 1-40 kg/cm2, 5-20 kg/cm2 or 10-20 kg/cm2, in particular 3-10 and particularly preferably 5-8 kg/cm2.
This pressure reduction is particularly advantageous for the industrial-scale preparation process, since the safety requirements which have to be met with respect to the pressure vessels used can be reduced. The cost-intensive use of high-pressure containers can thus be dispensed with.
Under the chosen process conditions, most of the palladium compounds used as catalyst are obtained as elemental palladium, and they can be removed from the reaction mixture is a simple manner by filtration. Thus, concentration of the palladium-containing reaction solution for subsequent disposal and any incineration of residues, which is complicated from a technical point of view and involves high costs, can substantially be dispensed with. Because of this, recycling costs are reduced. The pore size of the precipitated palladium is 1-10 xcexcm, in particular 1-4 xcexcm. At lost costs, the palladium removed by filtration can be worked up to the corresponding palladium compounds, such as, for example, palladium chloride, since the recycling costs depend on the concentration of the palladium.
Suitable solvents for the reaction in process step g) are nitrites, such as benzonitrile and acetonitrile, amides, such as dimethylformamide, dimethylacetamide, tetra-C1-C4-alkylureas or N-methylpyrrolidone and preferably ethers, such as tetrahydrofuran, methyl tert-butyl ether. Particularly preferred solvents are ethers such as 1,4-dioxane and dimethoxyethane.
Suitable catalysts are palladium ligand complexes in which the palladium is present in oxidation state 0, metallic palladium, if appropriate on a support, and preferably palladium(II) salts. The reaction with palladium(II) salts and metallic palladium is preferably carried out in the presence of complex ligands.
A suitable palladium(0) ligand complex is, for example, tetrakis(triphenylphosphine)palladium.
Metallic palladium is preferably deposited on an inert support, such as, for example, activated carbon, silica, alumina, barium sulfate or calcium carbonate. The reaction is preferably carried out in the presence of complex ligands, such as, for example, triphenylphosphine.
Suitable palladium(II) salts are, for example, palladium acetate and palladium chloride. The reaction is preferably carried out in the presence of complex ligands, such as, for example, triphenylphosphine.
Suitable complex ligands for the palladium ligand complexes, or those, in the presence of which the reaction with metallic palladium or palladium(II) salts is preferably carried out, are tertiary phosphines, whose structure is represented by the formulae below: 
where n denotes the numbers 1 to 4 and the radicals R8 to R14 are C1-C6-alkyl, aryl-C1-C2-alkyl or, preferably, aryl. Aryl is, for example, naphthyl and unsubstituted or substituted phenyl, such as, for example, 2-tolyl, and in particular unsubstituted phenyl.
The complex palladium salts can be prepared in a manner known per se from commercially available palladium salts, such as palladium chloride or palladium acetate, and the corresponding phosphines, such as, for example, triphenylphosphine or 1,2-bis(diphenylphosphino)ethane. Many complex palladium salts are also commercially available. Preferred palladium salts are [(R)(+)-2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl]palladium(II) chloride, bis(triphenylphosphine)palladium(II) acetate and, in particular, bis(triphenylphosphine)palladium(II) chloride.
The palladium catalyst is generally employed in a concentration of from 0.05 to 5 mol % and preferably 1-3 mol %.
Amines N(Ra)3 of the formula XIII which are suitable for the process are tertiary amines, such as, for example, N-methylpiperidine, ethyldiisopropylamine, 1,8-bisdimethylaminonaphthalene or, in particular, triethylamine, and also trimethylamine.
Suitable potassium salts are, for example, potassium phosphate, potassium cyanide and, in particular, potassium carbonate. Advantageously, the water content of the potassium salt should be low. Accordingly, the potassium carbonate was generally dried at at least 150xc2x0 C. prior to use.
The amount of potassium salt used is advantageously at least 1 molar equivalent. Otherwise, the reaction proceeds more slowly and/or the intermediate Fries rearrangement does not go to completion, giving O-acylated pyrazole derivatives. Preference is given to using in each case from 2 to 4 molar equivalents and particularly preferably 2 molar equivalents of potassium salt, based on bromobenzene III.
In addition to the potassium salt, the reaction mixture is also admixed with an amine N(Ra)3 of the formula XIII in which one of the radicals Ra is phenyl or naphthyl and the other radicals Ra are C1-C6-alkyl. Preference is given to using from 1 to 4 molar equivalents, particularly preferably 2 molar equivalents, of the amine XIII, based on bromobenzene X.
For work-up, the reaction solution is generally introduced into water. If the reaction is carried out in a water-miscible solvent, such as 1,4-dioxane, it may be advantageous to remove some or all of the solvent from the reaction mixture beforehand, if appropriate under reduced pressure. Any solid components present are removed from the aqueous alkaline reaction mixture, and the pH is then adjusted to 2.0-4.5, preferably from 2.5-4.5, particularly preferably 3.5, by acidification with a mineral acid, such as, for example, hydrochloric acid or sulfuric acid, resulting in virtually complete precipitation of the product of value. The isoxazoline radical, in particular, is sensitive to hydrolysis. In processes for preparing benzoylpyrazoles carrying this radical, a pH of below 2 is advantageously to be avoided.
For the acylation in process step g), the following process conditions are preferably chosen: solvent: dioxane or mixtures of dioxane and acetonitrile. Temperature: 110-130xc2x0 C. Pressure: 5-8, preferably about 6, kg/cm2. Catalyst: palladium(II) chloride. Molar ratio of heterocyclic hydroxyl compounds (such as, for example, 5-hydroxypyrazole) to bromobenzene derivatives: 1-2, particularly preferably 1.0-1.2.
Alternatively to the synthesis route shown in scheme 1, the compounds of the formula X can also be prepared according to scheme 2 or 3 below.
Scheme 2 shows a possible synthesis route to the bromobenzene derivatives of the type of formula X using the synthesis of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole as an example. The individual process steps can be carried out similarly to customary standard methods. 
Scheme 3 shows a further possible synthesis route to the bromobenzene derivatives of the type of formula X. 
The bromination of compounds of the formula VI is carried out in a manner similar to the direct bromination of anilines. If the reagent used is tetrabutylammonium tribromide, a selective monobromination in the para position to the amino function can be achieved in some cases (Berthelot et al., Synth. Commun. 16 (1986), 1641). However, a general problem of such brominations is the formation of polybrominated products (Bull. Chem. Soc. Jpn. 61 (1988), 597-599). If, for example, the reaction of VI with tetrabutylammonium tribromide is carried out in a mixture of water and methanol, using calcium carbonate as base, a product mixture is obtained which contains approximately 25% of dibrominated by-product. Separation of the product mixture is critical in particular if the substituents present include isoxazole and/or isoxazoline radicals which, under the chosen reaction conditions, are to be considered as labile with respect to their redox properties.
We have now found conditions which permit the preparation of the desired product XIV in good yields, without the formation of more highly brominated by-products. According to the reaction conditions of the invention, the preferred reagent is tetrabutylammonium tribromide. The solvents used are haloalkanes, such as 1,2-dichloroethane or methylene chloride, alcohols, such as methanol, ethanol, n-propanol, isopropanol, aliphatic nitriles, such as acetonitrile, preferably acetonitrile. The preferred base is potassium carbonate. The brominated intermediates XIV can then be converted by various routes into the isoxazol-3-ylbromobenzenes X according to the invention. The steps for preparing compounds IX from XIV or compounds X from IX can be prepared by the processes already mentioned above.
However, alternatively, it is also possible to initially convert the anilines into the sulfonyl chlorides X.c (see Houben-Weyl, Vol. IX, p. 579-580). These can be converted into the alkyl sulfones by reduction of the sulfonyl chlorides, for example using sodium sulfite, via the stage of the sulfinic acids (see Houben-Weyl, Vol. IX, p. 306-307) and subsequent alkylation (see Houben-Weyl, Vol. IX, p. 231-233). The two steps can advantageously be combined in a xe2x80x9cone-pot reactionxe2x80x9d. The advantage of this synthesis is the use of favorable reagents for introducing the alkylsulfonyl groups.
The step of the oximation of substituted toluenes used in process step a) of the process according to the invention is a novel and advantageous process for converting toluene derivatives into benzaldoximes. In principle, this process is suitable for producing benzaldoximes of the formula XV 
in which the radicals are as defined below:
X is NO2, S(O)nRy,
Rx is any inert radical;
Ry is any inert radical;
m is 0, 1, 2, 3 or 4,
n is 0, 1 or 2.
Rx, Ry are any organic radicals, which can be identical or different and which are chemically inert under the chosen reaction conditions. Examples which may be mentioned for Rx are: halogen, such as, for example, chlorine, bromine or iodine; carboxyl; carboxamide; N-alkylcarboxamides and N,N-dialkylcarboxamides; phenyl; C1-C6-alkyl, such as, for example, methyl, ethyl; C1-C6-alkoxy; C1-C6-alkylthio or other radicals. If m greater than 1, Rx can in each case be identical or different. Rx preferably has the same meaning as R1 and is located ortho to the oxime group xe2x80x94CHxe2x95x90NOH. m is in particular the number 2, one of the substituents Rx having the same meaning as R1 and the other substituent Rx being a halogen atom, which is preferably located in the position meta to the oxime group. Ry is preferably C1-C6-alkyl, for example methyl, ethyl, propyl.
Preferred compounds XV are those in which X denotes the group SO2xe2x80x94Ry and m is the number 2. In this case, one of the radicals Rx is preferably halogen (for example bromine or chlorine) and is located in the position meta to the oxime group. The second radical Rx is preferably C1-C6-alkyl (for example methyl, ethyl) and is located in the position ortho to the oxime group.
According to the invention, compounds of the formula XVI (o-nitrotoluene or o-alkylsulfonyltoluene) 
in which the substituents are each as defined above, are reacted with an organic nitrite of the formula Rxe2x80x94Oxe2x80x94NO, as already defined, under action of a base.
The nitrosation of o-nitrotoluene has been described in the literature (Lapworth, J. Chem. Soc. 79 (1901), 1265). However, even in this early work, a dimeric by-product is mentioned. Later works only describe the preparation of dimeric products under similar reaction conditions (Das et al., J. Med. Chem. 13 (1970), 979). A repetition of the experiment described in the literature with o-nitrotoluene shows that small amounts of 2-nitrobenzaldoxime are indeed formed.
If the conditions described are applied to 3-nitro-o-xylene, the dimer XVIII is obtained exclusively. 
For Michael additions proceeding under similar conditions, too, there is a note in the literature that they do not succeed with 3-nitro-o-xylene (Li, Thottathil, Murphy, Tetrahedron Lett. 36 (1994), 6591). According to the prior descriptions, it is therefore unexpected that benzaldoximes can be prepared from 6-substituted 2-nitrotoluenes in excellent yields. Moreover, we have surprisingly found that alkylsulfonates (Xxe2x95x90SO2Ry) can also be oximated under similar conditions at the methyl group in the o position. The compounds prepared by the process of the invention are important intermediates for preparing active compounds for crop protection agents (WO 98/31681).
The reaction is preferably carried out under the following conditions: the solvents used are: dipolar aprotic solvents, for example N,N-dialkylformamides, N,N-dialkylacetamides, N-methylpyrrolidone, preferably: DMF, NMP. The temperature is from xe2x88x9260xc2x0 C. to room temperature; preferably from xe2x88x9250 to xe2x88x9220xc2x0 C.; particularly preferably xe2x88x9235 to xe2x88x9225xc2x0 C. To achieve a sufficiently low melting point of the solvent system, it is also possible to use mixtures of solvents, such as, for example, with THF. Preferred nitrites or alkyl nitrites are n-butyl nitrite and (iso)amyl nitrite. Suitable bases are: (M=alkali metal): Moalkyl, MOH, RMgX; preferably KOMe, NaOMe, potassium t-butoxide. When using sodium bases, preference is given to adding 1-10 mol % of amyl alcohol. The stoichiometry is as follows: 1-4 equivalents of base, 1-2 equivalents of Rxe2x80x94ONO; preferably: 1.5-2.5 equ. of base, 1-1.3 equ. of RONO (i.e. an organic nitrite), equally preferably 1-2 equivalents of base and 1-1.3 equivalents of Rxe2x80x94ONO. The order of the metered addition: a) compound of the formula XVI and nitrite are initially charged and the base is metered in. b) To avoid metered addition of the solid base, the base can be initially charged in DMF, and compound of the formula XVI/nitrite can be added simultaneously. It is advantageous to meter in the base over a prolonged period to reduce the cooling that is required.
Work-up is carried out, for example, as follows: a) precipitation by stirring the mixture into water/acid e.g. water/hydrochloric acid. b) Precipitation by addition of a sufficient amount of water/acid. Suitable acids are mineral acids, such as sulfuric acid, hydrochloric acid or phosphoric acid, or else carboxylic acids, such as acetic acid. Purification of the product: by extraction with toluene at from 0 to 110xc2x0 C., preferably at room temperature.
If the reaction is carried out at elevated temperature (from xe2x88x9210 to 0xc2x0 C.) and the mixture is subsequently stirred at room temperature, work-up gives the benzonitriles directly. It is furthermore possible to liberate the aldehyde function from the benzaldoximes of the formula XV in the presence of an acidic catalyst and an aliphatic aldehyde e.g. aqueous formaldehyde solution. Suitable solvents are haloalkanes, such as 1,2-dichloroethane or methylene chloride, aromatics, such as benzene, toluene, chlorobenzene, nitrobenzene or xylene, polar aprotic solvents, for example N,N-dialkylformamides, -acetamides, N-methylpyrrolidone, dimethylpropylene urea; tetramethyl urea, tetrahydrofuran, acetonitrile, propionitrile or acetone, with or without addition of water. Particularly advantageous is aqueous acetone (from 1 to 20% of water), dioxane/water mixtures, and tetrahydrofuran/water mixtures. The reaction is carried out at from room temperature to the reflux temperature of the solvent, preferably at from 30 to 70xc2x0 C. Suitable acids are mineral acids, such as aqueous hydrochloric acid, sulfuric acid or phosphoric acid, acidic ion exchangers, such as Amberlyst 15 or Dowex 50Wxc3x978.
In the case of the compounds of the formula XV, it is then possible to convert the oxime group xe2x80x94CHxe2x95x90NOH into the corresponding aldehydes (xe2x80x94CHO) or else into the corresponding nitrites (xe2x80x94CN). These compounds are important synthesis building blocks for preparing active compounds of the formula I (cf. WO 98/31681).
The thioalkylation step used in process step d) of the process according to the invention is a novel and advantageous process for converting aniline derivatives into thioether derivatives (thioalkylation of aniline derivatives). In principle, the process is generally suitable for preparing thioethers of the formula XIX 
where Rx is any inert radical, m is a number 0-5 and R2 is a C1-C6-alkyl group, which comprises reacting an aniline of the formula XX 
with a dialkyl disulfide of the formula VII
R2xe2x80x94Sxe2x80x94Sxe2x80x94R2xe2x80x83xe2x80x83VII
in the presence of a catalyst. Preferred catalysts are copper powder, in particular copper powder having a particle size of less than 70 xcexcm, or elemental copper in another form, such as, for example, turnings, wire, granules, shot or rods. It is also possible to use copper(I) salts, for example copper(I) chloride, copper(I) bromide or copper(I) iodide, copper(II) salts, or elemental iodine. Particular preference is given to using copper powder.
In the compounds of the formulae XIX and XX, Rx is any radical which is chemically inert under the chosen reaction conditions during the reaction with compounds of the formula VII. Thus, suitable groups Rx are, for example, the following groups: hydrogen, alkyl, haloalkyl, halogen, cyano, nitro, alkoxy, haloalkoxy, alkylthio or heterocyclic radicals as mentioned at the outset in the definition of R6. Suitable heterocyclic radicals are, in particular, unsubstituted or alkyl-substituted 5-membered heterocyclic saturated, partially saturated or aromatic rings from the group consisting of isoxazolines, isoxazoles, thiazolines, thiazoles, oxazoles and pyrazoles. The compounds of the formulae XIX and XX can carry one or more, preferably one, two or three, substituents Rx, which can be identical or different.
Rx is preferably a C1-C6-alkyl group, for example methyl, ethyl, propyl. m is preferably the number 1 or 2. If m is the number 1, Rx is preferably located ortho or meta to the group xe2x80x94Sxe2x80x94R2 (in the case of the compounds XIX) or to the amino group (in the case of the compounds XX). If m is the number 2, the second radical Rx is preferably located in the position ortho and meta to the group xe2x80x94Sxe2x80x94R2 or the amino group.
Thioethers of the formula XIX are useful intermediates for preparing active compounds in the chemical industry, for example for preparing crop protection agents (e.g. WO 96/11906; WO 98/31676) or for preparing drugs. A process for introducing alkylthio functions which is frequently used is the exchange of a halogen (EP 0 711 754). However, the process described therein has the disadvantage that it is limited to aromatics which are substituted by strongly electron-withdrawing radicals. Moreover, the preparation frequently requires high temperatures. Under these reaction conditions, other sensitive functional groups are chemically modified, giving rise to complex reaction mixtures whose purification is complicated and associated with high cost, and in certain cases it is no longer possible to remove the impurities at all. In addition, suitable precursors are also not always commercially available.
Methods for preparing arylalkyl sulfides from anilines are known, but these methods have serious disadvantages. The Sandmeyer reaction, for example, requires the use of equimolar amounts of copper alkylthiolate (Baleja, Synth. Commun. 14 (1984), 215-218). The yields obtained are typically only in the range of from 20 to 60%.
Another method that has been described is the reaction of aromatic amines with alkyl nitrites in excess dialkyl sulfide (Giam et al., J. Chem. Soc., Chem. Commun. 1980, 756-757). Here, there is the problem that, in some cases to a considerable extent, side reactions occur which result in poor yields and high expenses for product purification. Moreover, when the reaction was carried out in an inert diluent, it was observed that, after an induction phase, a very violent reaction which was difficult to control set in, thus excluding industrial use.
It is an object of the present invention to provide an alternative preparation process for thioethers.
We have found that this object is achieved by the preparation process according to the invention, which permits the preparation of aromatic alkyl thioethers from anilines in an advantageous manner. Using the process, it is possible to carry out the preparation in a simple, cost-effective and efficient manner, taking into account ecological and economically advantageous aspects.
According to the invention, the aniline is reacted with a dialkyl disulfide and an organic nitrite Rxe2x80x94ONO following the reaction scheme shown above in the presence of a catalyst, preferably of elemental copper. Comparative experiments show that, using the conditions according to the invention, considerably better yields are obtained and less by-products are formed than without a catalyst. Moreover, the reaction is easy to control and can be employed industrially.
The reaction is carried out using the reaction conditions described in more detail below: suitable solvents are haloalkanes, such as 1,2-dichloroethane or methylene chloride, aromatics, such as benzene, toluene, chlorobenzene, nitrobenzene. Alternatively, it is also possible to employ an excess of the dialkyl disulfide itself as solvent. This variant is particularly advantageous. The reaction is carried out at from 40xc2x0 C. to 150xc2x0 C., preferably from 60 to 100xc2x0 C. and in particular from 70 to 90xc2x0 C. It may also be advantageous to carry out the reaction in a temperature range of 45-70xc2x0 C., in particular in a range of 55-65xc2x0 C. In the reaction, it is advantageous to add a C1-C6-alkyl nitrite reagent. In this respect, suitable reagents are, for example, n-butyl nitrite, (iso)amyl nitrite or tert-butyl nitrite. The stoichiometry is in this case, for example, 1-3 equivalents of alkyl nitrite, preferably 1-1.5 equivalents of alkyl nitrite, particularly preferably 1-1.3 equivalents of alkyl nitrile. Suitable catalysts are copper powder or elemental copper in another form, copper(I) salts, for example copper(I) chloride, copper(I) bromide or copper(I)iodide, copper(II) salts, or elemental iodine, preferably copper powder or elemental copper in another form; copper salts are equally preferable. The reaction is carried out, for example, using the following stoichiometric ratios: if the reaction is carried out in a solvent: 1-3 equivalents of dialkyl disulfide, preferably 1-2 equivalents. If the reaction is carried out without an additional solvent, i.e. if the dialkyl disulfide is used as solvent: use of an excess of dialkyl disulfide or mixtures of dialkyl disulfides, which can subsequently be recovered by distillation. The product is purified, for example, by distillation or crystallization (for example from diisopropyl ether).
The present invention furthermore provides a process for preparing compounds X using the above-described process for the oximation of substituted toluenes XVI (cf. process step a)) and/or using the above-described process for the thioalkylation of aniline derivatives XX (cf. process step d)). In the reaction scheme 4 below, a suitable preparation process is described using the example of a compound X where R1xe2x95x90CH3, R2xe2x95x90CH3, R3xe2x95x90R4xe2x95x90R5xe2x95x90H. In principle, the process is also suitable for preparing compounds X where the radicals R1-R5 are as defined above. 
The invention is illustrated in more detail in the working examples below. Examples 1-9 relate to process steps a)-g). Examples 10-26 relate to the preparation of starting materials or intermediates or to corresponding comparative examples. Example 27 relates to the reaction sequence for preparing compounds X shown in scheme 4.